Sex differences in placental markers and later autistic traits

Abstract:

Autism and related neurodevelopmental traits are more prevalent in males. Placental complications are also more frequent in male pregnancies. It is unclear if sex differences in placental function can predict sex differences in autistic traits. To assess this, concentrations of angiogenesis-related markers, placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1) were assessed in maternal plasma of expectant women in the late 1st (mean = 13.5[SD = 2.0] weeks gestation) and 2nd trimesters (mean = 20.6[SD = 1.2] weeks gestation), as part of the Generation R Study, Rotterdam, the Netherlands. Subsequent assessment of autistic traits in the offspring at age 6 was performed with the 18-item version of the Social Responsiveness Scale (SRS). Associations of placental protein concentrations with autistic traits were tested in sex-stratified and cohort-wide regression models, controlling for various confounders including placental weight. Mediation analysis was conducted to study if placental proteins mediated the effects of biological sex on autistic traits in childhood. sFlt-1 levels were significantly lower in males in both time-points but showed no association with autistic traits. PlGF was significantly lower in male pregnancies in the 1st trimester, and significantly higher in the 2nd trimester, thus levels increased faster in males during gestation. Higher PlGF levels in the 2nd trimester and the rate of PlGF increase were associated with higher autistic traits in linear regression models (PlGF-2nd : n = 3469,b = 0.24[SE = 0.11], p = 0.03). In sex-stratified analyses, these associations were significant in females but not males. Mediation analyses showed that higher autistic traits in males were partly explained by higher PlGF or a faster rate of PlGF increase in the second trimester (PlGF-2nd : n = 3469, ACME: b = 0.006, [SE = 0.002], p = 0.004). In conclusion, placental sex differences in PlGF levels are linked to sex differences in autistic traits.